The goal of this SBIR Phase I proposal is to develop force spectroscopy (F-SPEC) as a tool for drug discovery and high throughput molecular screening and analysis. F-SPEC is based on direct measurement of molecular interactions using an ultra-sensitive biosensor created by biomolecular functionalization of an Atomic Force Microscope (AFM) probe. Phase I will focus on the G-protein Ras, a key protein in 30% of all cancers. Farnesylation of Ras is required before it can associate with the membrane for signal transduction, making competitive inhibitors of farnesyl transferase (FT,) attractive as cancer fighting drugs. Specific Aim 1 is to show by F-SPEC that a difference in the interaction between Ras and farnesyl transferase (FTase) can be measured while an inhibitor is present versus absent Abnormal Ras GTPase activity is often related to mutations involved in oncogenesis. Specific Aim 2 is to develop a method using F-SPEC to distinguish wild-type from mutant Ras based upon binding interactions with GTPase Activating Proteins (GAPs) in the presence or absence of GTP. If Phase I is successful, F-SPEC will be implemented as a high throughput drug discovery and molecular diagnostic technology in Phase II and beyond. PROPOSED COMMERCIAL APPLICATIONS: The technology to be developed in this research program will provide a rapid and ultra-sensitive method for screening potentially useful compounds as drugs, and for testing differences in wt and mutant gene products involved in cancer and other diseases.